Breast cancer is one of the leading causes of morbidity and mortality in women worldwide. DNA repair pathways have been identified as a potential target for chemotherapeutic intervention of breast cancer growth. Normal cells actively repair DNA damage before going into mitosis and avoid DNA damage-induced killing of cells. In contrast, cancer cells possess defective mitotic signals and override the G0/G1 check point, but arrest in G2/M phase and face mitotic catastrophe and death.
Several DNA-alkylating drugs which induce DNA damage, such as Temozolomide (TMZ) and chloroethylnitrosoureas (CNU, BCNU, and ECNU), are listed in clinical trials. DNA damage induced by these alkylating drugs are primarily repaired by DNA polymerase β (Pol-β)-directed base excision repair (BER) pathway or the O6-methylguanine DNA-methyltransferase (MGMT)/mismatch repair (MMR) pathway.
TMZ's utility as a breast cancer treatment is limited by life-threatening adverse events, such as thrombocytopenia (an abnormally low number of platelets, which help blood to clot), which occurs at the doses required to achieve efficacy, as well as unpleasant side effects, including fatigue, nausea, vomiting, anorexia, constipation, headache, and alopecia (hair loss). Methods for reducing TMZ dosage and enhancing chemotherapeutic efficacy are urgently required.
The development of new therapeutic approaches that exploit the expression of certain molecules (e.g., estrogen receptor, progesterone receptor, and human epidermal growth factor-2 receptor) has proven effective. At present, no effective treatment exists for breast cancers that do not express the estrogen receptor, progesterone receptor, and human epidermal growth factor-2 receptor. Such tumors are termed triple-negative (ER−/PR−/HER2− breast cancers, and are associated with a high rate of local and systemic relapse.